Meyskens F L, Gerner E W
Department of Medicine, University of California, Irvine, Orange 92668, USA.
J Cell Biochem Suppl. 1995;22:126-31. doi: 10.1002/jcb.240590816.
Experimental studies have demonstrated that carcinogenesis is a multistep process in which inappropriate proliferation of cells is a critical determinant. Polyamines support sustained growth and are highly regulated in all cells. The rate limiting enzyme for this pathway is ornithine decarboxylase (ODC), an enzyme that exhibits rapid turnover, and converts the amino acid ornithine to putrescine, which in turn is converted to the longer chain amines spermidine and spermine. In animal models of colon carcinogenesis, inhibition of ODC by difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor, reduces the number and size of colon adenomas and carcinomas. DFMO was first ineffective when used clinically to treat acute leukemia or melanoma and caused clinically significant but reversible ototoxicity. Subsequently, we performed a series of analyses demonstrating that hearing loss was rare below a total cumulative dose of 150 gm/m2 and increased with total cumulative dose of DFMO. The hearing loss was reversible with rapid reversion to baseline hearing. We and others have conducted Phase IIa trials to determine the lowest dose at which DFMO can decrease colon mucosa polyamine content, and found that an oral dose as low as 0.25 gm/m2 per day (perhaps lower) decreases colon tissue putrescine content and lowers the spermidine/spermine ratio. We are currently conducting a long-term randomized Phase IIb trial which serially measures the long-term effect of several low doses (and placebo) of DFMO on sustaining polyamine depletion in colon mucosa, as well as carefully monitoring hearing by audiometry and other sophisticated tests.(ABSTRACT TRUNCATED AT 250 WORDS)
实验研究表明，致癌作用是一个多步骤过程，其中细胞的不适当增殖是一个关键决定因素。多胺支持持续生长，并且在所有细胞中受到高度调控。该途径的限速酶是鸟氨酸脱羧酶（ODC），这是一种周转迅速的酶，它将氨基酸鸟氨酸转化为腐胺，腐胺又依次转化为更长链的胺类物质亚精胺和精胺。在结肠癌发生的动物模型中，用二氟甲基鸟氨酸（DFMO）（一种酶激活的不可逆抑制剂）抑制ODC，可减少结肠腺瘤和癌的数量及大小。DFMO最初用于临床治疗急性白血病或黑色素瘤时无效，并引起具有临床意义但可逆的耳毒性。随后，我们进行了一系列分析，结果表明，总累积剂量低于150 gm/m2时很少出现听力损失，且听力损失随DFMO总累积剂量的增加而增加。听力损失是可逆的，可迅速恢复到基线听力水平。我们和其他人进行了IIa期试验，以确定DFMO能够降低结肠黏膜多胺含量的最低剂量，发现每天低至0.25 gm/m2（可能更低）的口服剂量可降低结肠组织腐胺含量并降低亚精胺/精胺比率。我们目前正在进行一项长期随机IIb期试验，该试验连续测量几种低剂量（和安慰剂）DFMO对维持结肠黏膜多胺消耗的长期影响，并通过听力测定和其他精密测试仔细监测听力。（摘要截选至250字）
